TB R&D Weekly Update: Stepwise Mutation in Clinical Isolates Supports Current TB Therapy

Saunders NJ, Urmi HT, Thomson ML, Doig C, Laurenson IF, Blaxter ML. Stepwise mutation to multiple drug resistance in Mycobacterium tuberculosis in an otherwise stable genetic backgrounddoes not support models of high mutation in the host and emphasizes the need for maintained effective concentrations of multiple antibiotics. J Infect. 2011 Jan 12. [Epub ahead of print]

Deep re-sequencing, a technique that allows a determination of a causal mutation, was used to explore the emergence of resistance to TB therapy and to take a closer look where and how mutations related to drug-resistance arise during natural infection. Previously, in vitro studies pointed to higher rates of mutation, hypermutability, in Mycobacterium tuberculosis than seen in other bacterial strains as the basis for the emergence of drug resistant strains in TB. Based on the in vivo study by Sanders, et al., there is no evidence that this hypermutability exists for M. tb.

A series of three isolates were obtained from a 56 year old HIV negative man who did not comply with TB therapy. Isolates were obtained over a 12-month period starting at the time of initiation of treatment when bug was still drug-sensitive to 9 months when the bug became resistant to isoniazid to 12 months when the bug became resistant to both isoniazid and rifampicin. Only two point mutations were identified between the three isolates corresponding to each change in drug-resistance. The single mutation observed in the INH-resistant isolate was the one most commonly found in IHH resistant clinical isolates. This was also the case for the mutation identified for the RIF-resistant isolate which was found in the region where 95% of the mutations for RIF-resistant clinical isolates are found.

An interesting observation noted by the authors noted that “monoresistant RIF-resistant strains are more readily killed by isoniazid, than monoresistant INH-resistant strains are by rifampicin,” so “the emergence of rifampicin resistance would thus be expected to follow that of isoniazid resistance simply through the process of selection following survival of the INH-resistant population during sub-optimal therapy.” The authors concluded the following:

  • Order and frequency of resistance is reflective of relative efficacy of the antimicrobial agents
  • Resistance is associated with the size of the bacterial population and the duration of colonization contradicting the results seen in vitro.
  • Keys to optimal therapy are use of multiple drugs with the greatest individual efficacy
  • Treatment regimens must maintain therapeutic concentration over a period greater than or equal to the rate of bacterial cell division
  • Isonaizid monotherapy for treatment of latent TB may be ill-advised
  • Studies such as the one presented may be useful in understanding the selection and adaptive responses of bacterial pathogens during natural infection

In other R&D news:

Collaborative Drug Discovery Receives New Funding to Support Tuberculosis Drug Discovery Screening Efforts and Industrial-Academic Collaborations

Phase IIb randomized trial of adjunct immunotherapy in patients with first-diagnosed tuberculosis, relapsed and multi-drug-resistant (MDR) TB

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